Essential tremor (ET), the most common movement disorder in humans, significantly compromises the livelihood or social function of at least 85 percent of the 4 million individuals affected with the disease in the United States. Aggravated by emotions, hunger, fatigue and temperature extremes, the condition may cause a functional disability or even incapacitation. The main clinical feature of ET is postural tremor of the arms, but the head, legs, trunk, voice, jaw, and facial muscles also may be involved. The majority of cases are familial and the disease is usually an autosomal dominant trait with incomplete penetrance. The identification of two susceptibility loci on chromosomes (chr) 2p22-p25 (ETM) and chr 3q13.1 (FET1) implies that ET is genetically heterogeneous. We originally identified the ETM locus in a single American family of Czech descent with pure ET, and later refined the location of the ETM gene to 9.1 centiMorgan region by genotyping three additional families with a similar phenotype. The long-term objectives of the proposal are to identify the other ET susceptibility loci by linkage analysis and to characterize these genes by positional cloning techniques. The specific aims are the following: 1). Collect additional individuals and families with ET. 2). Define the minimal critical region (MCR) that contains ET genes by identifying key recombinants. 3). Construct a high-resolution physical map (contig) of the MCR. 4). Isolate the genes within the contig and evaluate these candidates for disease-causing mutations. The results of this research will enhance our understanding of the human motor system in general and the pathogenesis of tremor in particular. Because current pharmacological treatments for ET have limited efficacy and often become ineffective with advancing disease, identifying the genes that cause ET will facilitate the development of more effective therapeutic strategies.